Methylation of curare



Patented Jan. 8, 1952 s l I ini'rHYLA'rIoNoF comma Malcolm D. Bray, Noblesv ille, Ind., assignor to Eli Lilly and Company, Indianapolis, -Ind. a

corporation of Indiana p This invention relates to; the preparation of lissive-active derivatives of curare alkaloids and more particularly to the methylation of d-tubocurarine in tubocurare. I f

The preparation of d-tubocurarine dimethyl" ether chloride and iodide from pure,;crystalline d-tubocurarine chloride has been described by King [J. Chem. Soc. 138, 1381 (1935)] and Dutch- Application Nov f 4 V ,5 Serial No. 125,398 p s v w evaporating the reaction mixture to a small 'volume and cooling the concentrated solution,

whereupon crystals of .thes'alt of 'the dimethyl .er [J. Am. Chem. $00.68, 419 (1946) 1. However,

'the pure d-tubocurarine chloride used as the 'starting material in the above-mentioned syntheses is very difiicult to obtain for its preparation requires comp1icated,"costly and inefficient procedures. Therefore, thosemethods of obtainling the methyl ether, oijcurare, which require pure d-tubocurarine chloride as the starting material are not suitable for the preparation of the I dimethyl ether of tubocurarine in the quantities required for widespread therapeuticapplication.

An object of my invention is to provide a simple process of obtaining pure, crystalline, methylated d-tubocurarine hydroxide and, salts, Other objects will be apparent fromthe followingdescrip- .above' fand 'other obtion of my invention. 7

In accordance with the jects, dimethylated d-tubocurarine hydroxide and dimethylated d-tubocurarine salts are ob- 'tained directly and in good yield from tubocurareby treating the tubocurare with an alcoholic alkali solution, removing ,the alkali-insoluble fraction, and reacting the alkaline alcohol solution containing the curare'alkaloid with a methyl ester of an inorganic acid, e. g.', methyl sulfate, methyl iodide and the like. The corresponding salt of the dimethyl ether of thjd-tubociurarine .which is formed by the reaction can be isolated in the vform of the particular 'salt which is produced in the reaction mixture or, if desired, can be converted into dimethyl d-tubocurarine hy droxide or into a diilerent salt, and isolated in suchiorm'. Y

Illustratively, the practicezof my invention is carried out in accordance with the general. procedure'described belowi Crude tubocurare is mixed with a lowenmonohydric alcoholic solution of a strong alkali, and the mixture is heated for a short period of time to dissolve substantially all of the lissive-active alkaloid present. The insoluble, inactive portion is then separated, and to the solution which contains the active alkaloidal material is added an equivalent or more of the methylating agent. The solution is then heated until substantially complete methylation of the tubocurare has taken place. The methylated product is isolated by -which strong alkalies are soluble. used is a strong alkali which is soluble in' the selected alcohol, for example, sodium hydroxide peratmospheric pressures.

relative insolubility of the I d-tubocurarine di- ,ether of d-tubocurarine are formed.' The dimethyl ether salt crystals are filtered ofi, washed with a small volume of cold alcohol, and purified by recrystallization from a suitable solvent.

The dimethyl etheroi d-tubocurarine hydroxiide can be obtained by adding. to the reaction mixture an excess of a concentrated solution of strong alkali, thereby forming d-tubocurarin e dimethyl, ether hydroxide, and evaporating the reaction mixture until the hydroxide'precipitates. The hydro'xidewhich is isolatedcan be converted 'to salts of tubocurarine dimethyl ether by treatment with acids. For example, treatment'of the hydroxide with phosphoric acid yields d-tubocurarine dimethyl ether phosphate.

The curare materials which serve as starting materials in the process of my invention are the crude, tarry tubocurare of commerce, and the 'partially'purified dried tubocurare preparations which are commercially available, the latter generally being dark brown powders containing from 20 to 40 per cent of d-tubocurare. Also, there can be employed the relatively less crude Ipr'epara- 'tionof tubocurare such as that obtained 'bythe method described in. United States Patent No. 2,453,873 issued November 16, 1948 to F; A. Steldt.

The alcohol'used in preparing the alkali solution for the purpose of my'invention can beany of the lower 'monohydric aliphatic alcohols in The alkali or potassium hydroxide; The latter is especially suitable because of itsready alcohol solubility. The alkali is used in a concentration from about "0.1 N'to about 2"N. For convenience" of preparation and use, I prefer to, use 0.5 Nalkalibut characteristics ofthe alkaliselected The methylating agent used is a methyl ester of an inorganic acid, for example, methyl or dimethyl sulfate or methyl chloride, methyl bromide or methyl iodide. Methyl iodide is the methylating agent of choice because of its reactivity and because of its higher boiling point which makes unnecessary the employment of su- Furthermore, the

methyl ether iodide which is formed in the :methyl ether iodide precipitates.

.ta-terisflltered aid. and dissolved in boiling water. ;.The,. hot solution is. treated Witha small amount Example 1 Preparation lOf crystalline rl-tubocurarine dimethyLetheriodideifrom crude tubocurare.-

50 g. of crude, tarry curare as received in commerce and containing about percent of d-tubocurarine are suspended in 400 cc. of 0.5 N methanolic potassium hydroxide, and the "mixture is boiled for ten minutes. Theflarkbrowninsolu ble material is filtered off and the ffiltrate 115 7 treated with 50 cc. of methyl iodide and refluxed gently forabout 8 hours. Anadditional amount of cc. of methyl iodide is addedto'thereaction mixture and the refluxing is continued 'for 8 hours. The reaction mixture is evaporated to small volume, whereupon the d-tubocurarine di The precipiof decolorizing carbon, the. carbon filtered off. and thelfiltrate cooledto. about 0 C. The dimethyl .-..ether .of .d-tubocurarine iodide crystallizes in white crystals which melt at about267-270" C.

with decomposition.

' Usin'gthe quantities indicated above, 9.75 g.-of

the dimethyletherof d-tubocurarine iodide were portions, 4 cc. of dimethylsulfate, and the mixture is allowed to stand at room temperature for about 2 hours. The reaction mixture is cooled to about 0 C. and while cold is treated with an excess of concentrated sodium hydroxide solution. The mixture is evaporated to about half its volume sand the precipitate "of id-tubocurarine dimethyl ether'hydroxide which forms is filtered The precipitate is suspended in several cc. Water and is treated with a slight excess of phosphoric acid and the mixture is then cooled to about"0"C., the crystalline d-tubocurarine di- .methyl ether phosphate is filtered oil, and re- .crystallized'from a small amount of boiling water.

Example '4 iPreparatlonof'd-tubocurarine dimethyl ether cloride from partially purified curare.

theoretically obtainable .from the detubocurarine V eexperimentally determined to be present inthe curare. Analysisoithe'dimethyl ether thus re- .pareiishowed.thapresenceot 2.90 percent nitrogentas compared with calculated amount of 3.0 percent.

Eram leiz Preparation of "crystalline d-tubocurarine di- *methyl ether iodide. :'5 g. of dried "tubocurare containing about 20 percent of d-tubocurarine. aresuspended in 50 cc. of a 0.5 'N solution of sodium'hy'droxide'in 95 percent ethyl alcohoL-and the mixture is gently.

refluxed for :about l0 liminutes; "The insoluble 'material is filtered Jolt-the filtrate istreated with cc of methyriodide and'the mixture refluxed for about 8 hours. An additional amount of 3. cc. of methyl iodide isadded to the reaction mixture :and refluxing' is continued for 8 hours. The reaction mixture then evaporated .to a small volume whereupon the'wdimetehylether of d-tubocurarineiodideprecipitates. The precipitate is filtered oil and purified according to the proc dure described in Example1.

Example 3 Preparation of d-tubocurarine dimethyiether .;i hosphate.

"Thefprocedure of Example 2 is followed except that methyl chloride is used in place of methyl iodide, and the reaction-mixture is heated-in a pressuretubeatabout60 C. for about 14' hours.

1. The method of methylating tubocurare which comprises treating tubocurare with alower monohydric alcohol solution of a :strong alkali, removing the alcoholic alkali-insoluble portion, and heating the alcoholioalkali solution with a methyl ester of an inorganicxacld.

.2. The method of obtaining methylated curare which comprises reacting the alcoholic alkalisolubleportionzofitubucurare.with a methyl ester of an inorganic acid.

H3. The process of 'obtaininga d-turbocurarine dimethyl ether salt whichcomprises treating tubocurare with a lower monohydric alcohol solution. of a strongalkali, removing the alcoholic alkali-insoluble portion, heating the alcoholic 'alkali-solubleportion with a methyl ester of an inorganic acid, and'evaporating the reactionmixture to a reduced volume to cause pre cipitation of the d-tubocurarine dimethyl ether salt.

4. The method of obtaining 'd-tubocurarine dimethyl ether .iodide which comprises treating 'd-tubocurarine with alcoholic alkali, separating the alcoholic'akali-sinsoluble portion, heating the alcoholic alkali-soluble portion with methyl iodide, and recovering the d-tubocurarine dimethyl ether iodide. v a

5. In the method of preparing d-tubocurarine methyl ether iodide according to claim 1, the step of reacting thealcoholic.alkali-soluble portion of tubocurare with methyl iodide.

"MALCOLM D. BRAY.

- REFERENCES; CITED The following references are of record in the fileo'f this patent:-' r f "Dutcher: J. Amer. Chem'aSoc, vol. 68, pp.-419- to. of 

3. THE PROCESS OF OBTAINING A D-TURBOCURARINE DIMETHYL ETHER SALT WHICH COMPRISES TREATING TUBOCURARE WITH A LOWER MONOHYDRIC ALCOHOL SOLUTION OF A STRONG ALKALI, REMOVING THE ALCOHOLIC ALKALI-INSOLUBLE PORTION, HEATING THE ALCOHOLIC ALKALI-SOLUBLE PORTION WITH A METHYL ESTER OF AN INORGANIC ACID, AND EVAPORATING THE REACTION MIXTURE TO A REDUCED VOLUME TO CAUSE PRECIPITATION OF THE D-TUBOCURARINE DIMETHYL ETHER SALT. 